BIODEGRADABLE POLYANHYDRIDE DEVICES OF CEFAZOLIN SODIUM, BUPIVACAINE,AND TAXOL FOR LOCAL-DRUG DELIVERY - PREPARATION, AND KINETICS AND MECHANISM OF IN-VITRO RELEASE

The overall objective was to design and evaluate biodegradable implant s for local drug delivery in clinical conditions and/or diseases descr ibed below, which are currently treated with systemic administration o f drugs. Local delivery of cefazolin is desired in conditions such as osteomyelitis, soft-tissue infection and for prevention of post-surgic al infections. Similarly, implanting a biodegradable device loaded wit h taxol in the cavity created by tumor resection will provide high loc al concentrations of taxol killing the malignant cells which may have survived the surgery, thus preventing metastasis and regrowth of the t umor and also prevent the systemic side effects of taxol. Prolonged re versible nerve blockade required in a number of clinical situations in volving acute or chronic pain such as post-surgical pain following her niorrhaphy and thoracotomy can be achieved with local delivery of bupi vacaine. Therefore, disk-shaped implants of polyanhydride, P(FAD-SA, 5 0:50 w/w), loaded with 10% w/w of cefazolin sodium, taxol and bupivaca ine were prepared and evaluated for content uniformity and in vitro re lease characteristics for the above mentioned local drug delivery appl ications. All of cefazolin sodium was released in 14 days while 90% bu pivacaine was released in 35 days. In striking contrast, taxol was rel eased very slowly, and only 15% taxol was released in 77 days. The ove rall release appeared to be following first order kinetics, and the in itial linear profile was fitted to zero order kinetics to obtain relea se parameters. Since cefazolin is highly water soluble and bupivacaine is moderately water soluble, compared to taxol which is extremely lip ophilic, the aqueous solubility of the incorporated drug appeared to i nfluence its release characteristics. Very good correlation was observ ed between release parameters (A(o), k(o)) and the solubility and intr insic dissolution rate (IDR) of drugs suggesting that the hydrophilic/ hydrophobic nature of the drug influences its release from polyanhydri de devices. Since polyanhydrides are believed to undergo pure surface erosion, release of the incorporated drug should be independent of its physicochemical properties, however the results presented in this stu dy suggest otherwise. Therefore, P(FAD-SA, 50:50 w/w) may not be under going surface erosion, and that diffusion and dissolution properties o f the drug in addition to erosion characteristics of the polyanhydride appear to play a role in drug release. Implants prepared and evaluate d in this study released cefazolin, bupivacaine and taxol for a prolon ged duration of time; however, depending upon the desired duration of release, an appropriate polyanhydride will have to be selected. For ex ample, taxol was released so slowly that a more hydrophilic polyanhydr ide may have to be selected to release all the drug in a shorter perio d of time to be of any therapeutic use. Cefazolin implants released th e drug for a sufficient duration for osteomyelitis and soft-tissue inf ection but the release was more prolonged than required for prevention of post-surgical wound infection. (C) 1998 Elsevier Science B.V.